Fostering Communication and Collaboration
The nihCatalystA Publication for NMH Inira mural Scientists
Institutes of Healthb Office of the Dieectorb Volume 6 Issue 5 National , m Septembfr-October 1998
A Rocky Mountain The Last Best Place eor Research: Science Sampler NIAID ’s Big Sky Laboratory by Celia Hooper Bruce Chesebro, who heads the Laboratory of Persistent Viral Dis- magine living in Shangri-La—a shim- eases (LPVD), has a three-ring re- mering, legendary trout-stream river search focus: on the immunology of I valley poised between two spectacu- mouse Friend leukemia retrovirus, lar mountain ranges that make the win- neural HIV infection, and transmis- ters mild and the summers temperate . . sible spongiform encephalopathies . . A place where people don’t lock their or TSE diseases. houses or even bother to roll up their Retroviral immunology has been car windows, much less install The Club a 25-year interest of Chesebro’s. The .... A place where you can find park- Friend vims, which is in the same ing after 9:30 a.m. and you don’t even family of vimses as HIV, causes fatal need a sticker or a hanger. Now imag- leukemia in a high percentage of sus- ine that, in this paradise, you also get all ceptible strains of mice. Remarkably, the perks of being an intramural scien- other strains be- tist—the chance come infected but to do excellent re- “cure” their own search with good leukemia. “We support services know more about and bright, ener- a protective re- getic colleagues. sponse to this vi- It’s not a day- rus than to any dream; it’s the other retrovims,” Rocky Mountain Chesebro says. Laboratories. Celia Hooper He is closing in RML, a Hamil- from two direc- ton, Montana, out- Above the Mouta}ia Lab: the Bitterroots tions on under- post of NIAID, standing effective celebrated that cago and determined that the ailment immune response institute’s 50th an- was being spread by infected wood to Friend by at- niversary this ticks. State and federal public health tempting to de- summer. Tlje NIH officials, working out of a shack in the velop a vaccine Catalyst used this area, launched prevention and control MOUNTAIN WOOD TICK and by attempt- THE ROCKY as an excuse to pandora's box continued on page 6 ing to clone the visit the place and Rfv-3 gene on find out, if you CONTENTS mouse chromo- John Moore {circa 1955) will pardon the 1 5 some 15 that appears to confer the pun, what makes it tick. The Last Best Place Solid Start for effective immune response. Ulti- As RML scientist-emeritus Willy NIH Foundation Rocky Mountain mately, Chesebro expects, there will Burgdorfer (who discovered Borrelia Research Catalytic Reactions be three essential components: cor- burgdorferi, the spirochete that causes rect responses in CD8+ cells and Lyme disease) tells it, the facility that 2 11 Art Levine; Hot Methods: CD4+ cells and in humoral antibody would eventually become RML owes its Festival and Farewell Come-hither CVs production. origins to a mysterious western Montana For his work on HIV-dementia, outbreak at the turn of the century of 3 12 New NIDDK Lab Recently Tenured Chesebro collaborates with col- what was called black measles or spot- leagues at the Department of Neu- ted fever. As dozens of settlers and pio- 4 15 rology at Johns Hopkins University neers moving through the Bitterroot Val- Mentoring Roundtable Gazette/Cartoon School of Medicine in Baltimore, ley perished, Howard Taylor Ricketts was Poster Day: The coiitimied on page 8 SG 16 summoned from the University of Chi- Surprises Students Catalytic Questions — —
From the Deputy Director for Intramural Research: Guest Editorial
It’s as Good as It Gets: Very Personal Reflections on NIH and Its Research Festival
he Twelfth Annual NIH Research Festival arrives Natcher Building, making it easy to move between talks with all due pomp and circumstance—on October and workshops but forcing a cutback in the number of T 6-9. As chairman of this year’s festival, I have the workshops and posters—although we were still offered opportunity to continue what has become a wonderfully an amount and diversity of science that one could barely satisfying and still evolving tradition. However, this Re- metabolize. That year also, we began to involve NIH’s search Festival will have a bittersweet flavor for me per- growing library of “special interest groups” in festival sonally, as I shall be leaving NIH immediately after the organizing. In 1996, to celebrate the Tenth Research Fes- festival to become senior vice chancellor for the health tival, we revived Abner Notkins’ notion of inviting NIH’s sciences and dean of the School of Medicine at the Uni- most senior scientists—including several institute and versity of Pittsburgh. After 31 years at NIH, I cannot imag- scientific directors—to present posters. Despite the vast ine a better way to say hail and farewell to this great resources available to this august group, their posters institution than by celebrating its intramural science. while .scintillating, perhaps, scientifically—tended to lack The Research Festival has changed over the years, in the aesthetic of their younger but more Mac-proficient both style and content. My good friend Abner Notkins, colleagues. That year, too, after years of tolerating the then NIDR scientific director, proposed the idea to the September rains, and with a science-based consult (Poor Board of Scientific Directors in 1986. Abner now recalls Richard's Almanac), we moved the festival to early Oc- that back then, “We had 15 very separate, self-contained, tober; and last year, obeying Poor Richard and remem- and often isolated institutes. More than a little of the bering not to schedule the festival on Yom Kippur, we very good work going on in the different institutes was were rewarded by sunshine. Last year saw the birth of a similar or even overlapping, especially at the basic level, Postdoctoral Job Fair, am by the Office of Education, but investigators often had no sense of this common bringing together job-hunting postdocs and representa- ground because scientists in the various institutes simply tives of pharmaceutical and biotechnology companies.
didn't have much contact with one another.” In addition, I have again fine-tuned the formula for this year’s fes-
Notkins felt that the breadth and depth of excellent in- tival (the program is available at:
research, thought that the festival idea was worth a try. I believe this will be one of the most exciting scientific
The first year, Abner organized a one-day festival and se.ssions ever held at our festivals ( talks on astrobiology, decided to turn the usual protocol for scientific meetings planetary origins and prebiotic life, and the earliest events
on its ear. Instead of having the “supenstars” present the both in prokaryotic and eukaryotic evolution). plenary symposia, and postdocs their posters, he asked The Thursday plenary symposium offers a nontradi- Rail to invite NIH's most prominent senior scientists to tional view of translational research: bedside-to-bench,
present the po,sters. Thus, it was midcareer and even rather than the more customary bench-to-bedside. The younger scientists who headlined the morning program, last morning symposium is devoted to a subject now with plenary symposia on topics that at the time were at pursued aggressively in virtually ever)' institute: Apoptosis. the cutting edge: Prospects in Ge>ie Therapy and Mini-symposia on cross-cutting topics of interest to both Oncogenes and Growth Factors. Notkins recalls one Nobel basic and clinical researchers fill the mornings and poster laureate staiggling to a,ssemble his poster—something .sessions the afternoons. The latest lab equipment is on he'd never done before or, at lea.st, not for decades! The display throughout Thursday and Friday. The challenge festival's afternoon featured 20 workshops, with a gala will be to choose from the engaging menu of competing picnic concluding “Research Day” in the evening. Hardly sessions, including, for example, “Cell Biology of the the typical federal event! Nucleus” (chaired by Mary Dasso and John Hanover),
I chaired the second NIH Research Festival. Still just “Molecular, Cellular, and Tissue Imaging” (Peter Basser one day, this one included plenary symposia on Signal and Carolyn .Smith), “HIV Biology: Bridging the Gap Transduction. Gene Structure and Expression, and the Between In Vitro and In Vivo" (Edward Berger and Le- Molecular and Cellular Biology of the Nervous System. onid Margolis), and "The Molecular and Cellular Biology Again, we made time for a picnic and even a jazz con- of Diabetes Mellitus” (Abner Notkins and Phillip Gorden).
cert in the evening. Getting from one event to the next 1 hope you enjoy this thoroughly groaning board, filled proved daunting, given that the workshops were so with the fruits of our best basic and clinical science. For
widely scattered across the campus. myself, I know that the delight I shall take in this festival In 1990, the festival joined forces with the Technical will mirror the joy of my three decades at this magnifi-
Sales Association (an equipment vendors' trade organi- cent in.stitution. I may be moving on, but my deep affec- zation), which mounted a display of the latest scientific tion and respect for my many NIH colleagues will en- equipment in the tent that had earlier housed the post- dure. Despite the frustrations that we may feel (e.g., cam- ers. (The association’s generous role in the festival was pus space so supersaturated that we may all soon crys- the brainchild of Jim Bahre, for many years a tallize and .seemingly limitless government forms to com- manufacturer’s representative on this campus and so in- plete), surely there has not in history —been a better place extricably a part of our culture that he eventually re- than this one in which to do research “it’s as good as it ceived an NIH Director’s Award!) Successive festivals fol- gets”—and in the Twelfth Annual NIH Research Festival, lowed this model more or less intact through 1994. In we’ll know this still again. 1995, all festival events were con,solidated in the new —Arthur S. Levine, Scientific Director, NICHD S F P T F M U F 1< — O ( T O li !• U 1 9 9 S
hy Sbaro)i Ricks, New NIDDK Lab Concentrates the Spotlight tedviical miter. On Normal and Oncogenic Mammary Gland Development NIDDK
ay 11 was moving day for 11 novel gene called and in a short NIDDK researchers and 400 the whey acidic time, 99 percent of M mice—out of their friendly but protein (Wap)." the epithelial cells modest quarters in the upper reaches When Hennig- die.” He says the of the Clinical Center and into the new hausen came to lab will explore NIDDK Laboratory of Genetics and the NIDDK Labo- the signals that Physiology (LGP). ratory of Bio- trigger cell death The new lab spans rooms 101 through chemistry and Me- for clues on how 115 of Building 8 and boasts a new la- tabolism in 1985, to destroy tumors. ser-capture microscope (see “Hot Meth- he picked up the NIDDK Scien- ods: Laser Capture Microdissection,” research again tific Director Allen discovered NIH Catalyst, November-December, and Lothar Hennighausen (seated), encircled by Spie sel says 1997, page 12) and new video imaging that the Wap gene labmates (left to right): Ulrike Wagner. Hennighausen’s equipment. It officially opened June 11, was almost exclu- Svetlana Stegalkina. Kay-Uwe Wagner. work has illumi- replacing the developmental biology sively expressed Patricia Dierisseaii. Justin McShane, Ed nated the role of Rucker. Nataly Strunnikova. Robin section of the Laboratory of Biochem- in mammary tis- several hormones, Humphreys. Jonathan Shillingford. Gertraiid istry and Metabolism. sue and that its growth factors, Robinso)!. Aiune Guerrero, and Marta lab explores genetic switches control switches and their signal- The and Gallego. biochemical pathways that control nor- targeted other transduction path- mal and oncogenic mammaiy gland genes to mammary tissue for expression ways in the complex changes that occur development—and it’s a tribute to l6 in transgenic animals. The new promoter in the breast during normal pubertal de- years of study of mammary gland de- could therefore be used to target velopment, pregnancy, lactation, and in- velopment and physiology. (Though the oncogenes to mammary epithelial cells volution, as well as in the neoplastic pro- lab is dedicated to the study of the mam- and to create mouse models of human cess that leads to breast cancer. mary gland, other projects, such as the breast cancer, Hennighausen recalls. It Colleagues at NCI are quite interested study of germ-cell development in the could also be applied to the creation of in the work of the LGP. “Lothar’s lab is testes, are also on the agenda.) “mammary bioreactors” to express phar- working to identify all the genes that are The research originated in the quest maceuticals in the milk of transgenic expressed during normal mammary of a graduate student in Cologne, Ger- mice and livestock, such as are now used gland development and to define when many, who was commercially to produce blood-clotting they’re expressed,” says Bob Callahan, working on his factors in sheep chief of the Oncogenetics Section in thesis project in and goats. NCI's Laboratory of Tumor Immunology the genetics lab These days, and Biology. “His is probably the only in which the says Kay-Uwe lab doing that for any particular tissue,” lysozyme gene, a Wagner, a postdoc Callahan says, “and it provides a basis relative of the in the lab, “we are for understanding where things go wrong milk protein, a- doing tissue-spe- during mammary tumorgenesis.” lactalbumin, had cific gene knock- NCI supports two related Web sites: been cloned. The outs,” linking the NIDDK’s Mammary Gland Anatomy student wanted to Wap gene with an Project at isolate the a-lac- enzyme specific
The N 1 H Catalyst
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Mentoring Roundtable: by Marc Horowitz, Director, Surgeon General Reviews Differences Office ofLoan Repayment and Summer Research at NIH Focus ON Cultural Scholarship
he subject of mentoring commands a lot of attention at NIH; this summer, at a T specially convened Mentoring Roundtable—the first of its kind at NIH—the focus was on mentoring students from disad- vantaged or minority-group backgrounds. Sponsored by the Office of Loan Repayment and Scholarship (OLRS), whose Undergradu- ate Scholarship Program (UGSP)* supports stu- dents from disadvantaged backgrounds, the Ernie Branson
roundtable featured invited university faculty Uri Treisman holds aloft with more than 90 years of combined mentoring guidebook mentoring expertise and substantial experi- Adm. David Satcber Surgeon General, ence mentoring disadvantaged and minority science students. More than 100 and Rear Adm. Arthur Lawrence, NIH denizens—undergraduate and postdoctoral students, scientists, and ad- senior advisor, upon arrival at NLH’s ministrators—attended the roundtable. Sununer Research Program Poster Day. August 6. For more than two Guest panelists were Lawrence K. Alfred, professor of biology at San Diego hours, the surgeon general reviewed State University; Frank J. Talamantes, professor of biology at the University of the research efforts of nearly 400 NLH California at Santa Cruz; and Uri Treisman, professor of mathematics at the summer research students, including University of Texas at Austin. The roundtable was moderated by John F. Alderete, the 23 who had come to NIH under the professor of microbiology at the University of Texas Health Science Center at Undergraduate Scholarship Program San Antonio and president of the Society for the Advancement of Chicanos and ( UGSP: see stoiy this page), for whom Native Americans in the Sciences. Poster Day was the culmination of In his 25 years of working with Chicano students, Talamantes said, he’d ob- their 10-week experience here. served in many a deference to authority, a subdued demeanor in the presence of a generally acknowledged leader in the field. Such characteristics, he noted, could be a handicap in the world of scientific research. The mentor’s challenge with such students is to help them question authority without disrespecting their cultural values. In general, Talamantes emphasized, mentors need to take stu- dents’ concerns and problems seriously, listen carefully, and respect students’ individuality. But they also need to challenge students' ideas of what they want to do and help them explore other options. Treisman pointed to the learning environment as the critical factor in minority students’ achieving their science career goals. Successful mentoring, he said, is most often accomplished in educational programs in which mentoring is a group enterprise with strong support and leadership from the department chair and administration. Good mentors, he said, are able to define excellence in
their field, know how to achieve it, and share that information with their stu- dents. The most important mentoring tasks senior scientists can perform are to monitor student progress, publicly ask questions, and scrutinize students' lab practices, he said. Alfred emphasized “nurturing” to help students overcome fears and to foster in them a belief in their own academic abilities. He also recommended that links be established between NIH scientists and the university mentors of stu- dents in NIH programs. He posed two key questions: How can we get more faculty members, especially those with NIH research grants, involved in mentoring? How can mentoring outcomes be measured more effectively? Panel members agreed that mentoring must be a part of the broader mission of an institution and the responsibility of mainstream faculty members, especially if
disadvantaged students are to succeed in the field of biomedical research. "My heart is in my throat. L just told the Michael Gottesman, deputy director for intramural research, noted that NIH surgeon general about my research leadership—including Director Harold Varmus and NIDR Director Harold Slavkin, project. "Ramirez whispered moments who chairs the Committee for the Recmitment of Ethnically Diverse Young later. LLer poster depicting "Mobilizatioti Talent into Biomedical Research (also known as the Slavkin Committee), are ofCD8+ dowlritic cells in response to working to close the gap between students’ expectations and the reality of the microbial products as visualized by NIH research experience. A committee report and recommendations— imminiqfhiorescence microscopy her research in the hPAlD mentoring handbook—are expected by year’s end. reflected Laboratory ofImmunology' (with preceptor Ro)iald Germain). With her * Each student in the UGSP is assigned an NIH researcher to seiALe as a mentor. This mentoring relationship is initiated during a 10-week summer program, when students work as paid employees fresh SFSU degree in cell molecular in NIH research laboratories. A goal of the UGSP is continuation of the mentoring relationship into biology, Ramirez will pursue a doctorate all seasons. Marc Horowitz, director of the Office of Loan Repayment and Scholarship, Office of at the UGSP Program in Biological Intramural Research, oversees the UGSP and is always eager to identify intramural scientists willing Sciences beginning this fall. She learned to take active roles in mentoring his program participants, especially beyond the time spent in of the UGSP through the Societyfor the NIH's labs. Information on the UGSP can be found at
Foundation for the NIH Sets Off on Solid Ground
he National Foundation for Biomedical Research, also known as the Founda tion for the National Institutes of Health, is living up to the promise for which T it was designed by Congress. In the past year, the Foundation has started to become a magnet for donations from private-sector entities with an inherent interest in biomedical research, as well as from individual scientists who cherish NIH. Contributions approaching $2 million have been made to the Clinical Research Training Program (CRTP), the Foundation's first major initiative in collaboration with NIH, which aims to expose medical and dental students to the rigors and rewards of a career in clinical research. The CRTP is accommodating nearly twice
as many students in its second academic year (1998-1999) as it did the first time around, thanks to grants of $572,000 from Pfizer, Inc., to support 16 fellows, and $35,000 from the Ruch family foundation in New York, in honor of Foundation
Board member Mrs.William McCormick Blair, Jr., to sponsor one student. The Pfizer gift for total million. Marguerite Rippy (left). UGSP acting extends over two subsequent years a commitment of $1.6 director and Hosein Kouros-Mebr a The Foundation has received two grants from the pharmaceutical industry in hiocbeiuistiy majorat CalTecb. irbere support of the National Coalition for Health Professional Education in Genetics be stcnis bis sophomore year ibis fall. $25,000 from Novartis and $10,000 from Pharma. The Coalition includes more than Tins is tbe UGSP's third year. Rippy said, 100 professional organizations, government agencies, and consumer groups intent and tbe first year the program is at "full on ensuring that health professionals systematically keep pace with advances in strength. " About one in 12 applicants human genetics. NHGRl, the American Medical Association, and the American Nurses qualify for tbe program, ivhicb awards Association are among the coalition’s members. NHGRl director Francis Collins is a full tuition on a yearly basis for coalition co-chair. Moreover, the Merck Company Foundation has given a grant of successful candidates. After they earn 25,000 to support the foundation’s operations, a critical need as it grows. their advanced degree, pcuticipants The family of virologist Norman P. Salzman has established the Foundation’s provide a "one-yearpayback . " working first endowed memorial fund—the Norman P. Salzman Memorial Award in Virol- at NIH for each year qfsuppon they ogy, which will be awarded on a regular basis to an outstanding young postdoctoral received as an undergraduate. Koiiros- investigator in virology at NIH. Salzman’s research career spanned 40 years, many Mehr. who did research on the "struc- of them spent at NIH's Bethesda and Frederick campuses. The Salzman family has ture of the BfO.2 domain ofpyiin donated $15,000 to start the fund, and Salzman’s colleagues and friends have con- (irl50). under Daniel Kastner and tributed another $15,000, for a total of $30,000 thus far. Details about the award and Elizabeth Mansfield in the NIAuVIS the nominations process will be forthcoming; the first award will in Arthritis and Rheumatism Branch, be made 1999. further information aspires to a research career (PhD or For regarding the Salzman award, the CRTP, or making a MD/PbD) and a fiction-writi)ig sideline. donation to the Foundation, contact Anne Alexander, executive director. Building 1 Cloister Court, 301-402-5311. He 's already published shod stones and 60, Room 152, Bethesda, MD 20814; is working on a novel. Catalytic Reactions More Slide Tips I
Make multiple copies of a slide if it is to be used more than once in a presentation. | Avoid flipping back and forth during your talk. When at all possible, find out the | size of the room you're talking in and preview your slides in a similarly sized room. Stand in the back and look at your own slides. Always mark your slides so you can
easily place them in a cassette. As you hold the slide up to light to see it, make sure
you can read it with your naked eye. Then mark the lower left corner. When filling the cassette, the mark is in the upper right corner. \
—Barbara Vouderbaar, NCI \ On Teamwork \
I’d like to endorse, with enthusiasm, Michael Gottesman’s emphasis on the role of ’>
group dynamics in optimizing today’s biomedical research environment (“Fostering : Collaboration and Teamwork at NIH,” Catalyst. July-August 1998, p. 2). Andrea Borgbese. ivbo’s entering her Not only is the creative exchange among multidisciplinary teams of strategic im- I senior year at Lehman College. City portance in conquering diseases, those teams are expanding beyond the usual gov- U)uversity ofNew York, e.xplains her ernment-academia research collaborations to include corporate partners, as “inven- research to the surgeo>i general and tions” are viewed more as an integral part than a byproduct of biomedical research. Michael Gottesman. NIH deputy director Indeed, public demands for practical applications are often tied to funding authori- for i)itramural research. Her poster zations. Along with the advice that younger scientists working with more senior (*148) on "inducible transgenic mouse investigators “work cooperatively but carve a distinctive niche within the team," I models for autoimmune myositis" would add that they acknowledge the creative integrity of the contributions of their captures her work in the NIAAIS Aiihiitis colleagues well their readily credit the of others whether and Rheumatism branch with preceptors as as own and works — Paul Plotz and Kanneboyina Nagaraju. they are collaborators or not—that served as sparks to their own creativity. investigators are early in their experience "Amazi)ig, " Satcher said, as he wished One hopes that young introduced NIH her well. "He’s been impressed." to mentors who pay attention to group dynamics and foster teamwork in achieving commented Gottesman. wbo'd invited research goals—not to mention strict adherence to ethical principles. The value of Satcher to spend the day. the process and the people involved cannot be overstated. —photos and text by Fran Pollner — Wanda Darwin, OD/OHRM 5 —
s The N I H C a r a i r
The Last Best Place continuedfrom page 1 efforts. They went on to break important ground in understanding ticks and their anatomy and role in spread- ing diseases, as well as vec- tor-parasite relationships. These health officials even- tually produced a vaccine that prevented death from Rocky Mountain spotted fe- Yesterday: Tick-borne disease researchers, circa Vaccine development, circa 1925, in old ver. In the first three decades 1915. at precursor lab near Victor, Montana, run schoolhoiise lab. ( Caption information provided of the century, the lab pur- by the state and the Public Health Service. by Marshall Bloom. ) sued studies of five addi- tional tick-borne diseases: tick paraly- Kindt defines the focus of RML labs fairly work on Aleutian mink disease, sis, tularemia, Colorado tick fever, tick- broadly as being infectious disease, of- “couldn’t have been done elsewhere borne relapsing fever, and Q fever. In ten involving animal models. But beyond certainly not in Bethesda. For the bulk 1928, the lab—by then housed in a more that, he is loath to shoe-horn the re- of the animal work, this was the ideal modern research building—was sold to search into a narrower slot. Kindt says, place. You had or could get facilities the federal government. As far as as with the new lab chief being recmited [for research animals] right at the back Burgdorfer is concerned, “Tick-borne in the area of bacteriology, NIAID picks door.” Several senior scientists inter- diseases were and always will be the prime outstanding scientists “with their field in viewed by TJoe Catalyst cited the out- reason the [Rocky Mountain] Lab exists.” mind, but then we give them the free- standing animal research facilities as a But in the past 50 years, the lab’s fo- dom to follow the best research oppor- key factor in the success of their work. cus of research has tunities” just as To other scientists, various aspects of expanded beyond would be the case the locale are a definite advantage. In- tick-borne diseases. in Bethesda. The vestigator Tom Schwan, who studies RML’s fortunes have result is a slightly molecular adaptations of disease-caus- waxed and waned eclectic mix (see ing bacteria as they move from ticks to and right now seem “RML Science Sam- mammals, says the best thing about RML to be in ascendance: pler,” page 1) of is “having this type of research facility With a current staff of bacteriology, virol- in this type of environment.” Chesebro about 160, a massive ogy, and some im- says if he lived and worked elsewhere, $25 million renova- munology. “We like he’d probably use up more of his per- tion of the laborato- to keep the empha- sonal leave for vacation each year, ries and animal facili- sis on fewer rather whereas in Flamilton he can strike out ties is underway to than many things for prime recreation areas and be there bring them up to so that there is a in a matter of minutes after work or on modern building Celia Hoopei synergy among the the weekends. Chesebro is one of the codes. New staff, in- Bruce Chesebro (left) and Antony Basile groups” at RML, favorite rock-climbing companions of cluding a new lab Kindt says. “They Steve Porcella, a research fellow in the chief, are being recruited. RML scien- don’t cover every area that Laboratory of Microbial tists are excited about their research, and we do here in Bethesda.” Structure and Function visitors and would-be collaborators are If you ask scientists at and a semiprofessional venturing out to NIAID’s loveliest sum- RML what they like about rock climber who has mering grounds. For example, in mid- the place, for the most part published books and ar- July, Anthony Basile, a neuropharma- their answers are similar to ticles detailing ascents of cologist from NIDDK was out at RML to the answers you’d get from peaks in California and give a talk on his work and explore the satisfied researchers any- Montana. Marshall Bloom, possibilities of collaborating with RML’s where. For tenure-track in- an investigator who has Bruce Chesebro on studies of AIDS de- vestigator Sue Priola, the followed Hadlow’s tradi- mentia using a mouse model Basile has best thing about RML is tion in pursuing Aleutian developed. Basile’s lecture—one of five “the scrapie research mink disease, is an avid at RML that week—was enthusiastically group. We get along and angler and passionate lo- attended by a roomful of interested sci- interact well,” she says. “It cal leader in conservation. entists. “These people are all really top- is small, productive, with Some scientists mention Celia Hooper flight,” Basile said. “The best in their great exchange of ideas. times they were able to re- Bill Hadlou fields. I’ve been pleasantly surprised by The science is the biggest cmit a great postdoc either the high quality of the work.” plus.” Retired veterinaiy pathologist Bill because of the proximity of skiing and NIAID Scientific Director Thomas Hadlow says his research, including other outdoor attractions, or because an
(5 1> S F T E M 13 E 1( — O C T O li I- R 1 9 9 S
nual lab meeting of Stanford’s hematopoiesis pioneer, Irv 'Weissman.
'Weissman’s lab meeting is held on a nearby ranch that he shares with University of 'Washington (Seattle) scien- tist Leroy Hood and Nobel laureate David Baltimore, president of the California Institute of Technology in Pasadena. Kindt makes funds available to bring NIH Stipend goes farther in Montana than big cities, with a low crime rate and RML postdocs to Bethesda for the Re- Maryland. good public schools enlivened by en- search Festival and other meetings. “I But other staff—including librarian ergetic parent and teacher involvement. strongly encourage every fellow to come Kate Oliver who moved to Hamilton a From all signs, says Kindt, the com- to campus at least once during their tour year ago from Bethesda for the broad munity returns the lab’s affection, de- at RML,” says Kindt, who personally vis- challenges of running her own scientific spite the fact that RML scientists study its Hamilton two or three times per year. library—are happy enough to live in deadly diseases and rely on research As a result of these efforts, scientists lovely surroundings, but haven't become animals. Bloom believes that Montana at RML say that connectedness to pro- enmeshed in outdoor pursuits. Says culture, grounded in ranching, farming, fessional colleagues has been reduced
Kindt, "If it is necessary for you to go to hunting, and fishing, fosters an under- to a question of personality, just as else- the opera every week, you would not standing of the importance of disease where. “’With the electronic technol- live there, but otheiwise RML has pretty research and the correct presumption ogy—e-mail, videoconferencing—and much the same people” as Bethesda. that research animals will be treated hu- travel, isolation is now self-imposed,” “There may be more intense interest in manely. “The nice says Bloom. “I know the out-of-doors,” he adds, “but that is thing about [Hamil- people at the NIH not a necessary trait.” ton] is that there is a Bethesda campus Although Hamilton, with a population community involve- who are more isolated of about 4,500, may lack first-rate cul- ment that is very from what’s going on tural attractions and Bethesda’s diverse strong,” Kindt says. around them than
selection of great restaurants, there are Local newspapers people here. . . . It’s compensatoiy features, according to RML give extensive—and possible to be fully scientists. Bloom points out that more favorable—coverage connected here or to- academic and cultural opportunities are to lab events, includ- tally isolated there.” available in Missoula, about a 45-minute ing groundbreaking a Librarian Oliver says drive from Hamilton. And when artists year ago for the lab’s she has managed to and celebrities do come to the area—as renovation, at which get the RML library did Pulitzer Prize-winning author Jared the mayor of Hamil- well connected to Diamond in mid-July—there’s a much ton spoke. Kindt says electronic and interli- better chance of getting close to them RML staff have been brary loan resources and having a meaningful personal ex- updating the commu- from academic librar- change. “You don't get that at the nity progress on the ies in the region as Kennedy Center,” Bloom observes. renovation and how well as the NIH Li- Bloom sees the real advantage of RML’s construction may affect them. brary in Bethesda. The real problem is setting in the fact that its scientists are There are some disadvantages to life that for her personally, western Mon- very visible in the tiny community and at RML. A key concern for Kindt is keep- tana is remote from friends and fam- thus have a unique opportunity to com- ing RML scientists from being isolated ily—pretty much a full day’s journey municate science to the public. “You talk in their Shangri-La. Through frequent away. “There’s quite some expense get- about your work with people at the gas videoconferenced staff meetings, lab ting in and out of Montana,” says Oliver. station, the grocery, the bait shop,” chiefs’ meetings, and other formal and Researcher Schwan concurs: “The worst Bloom says. "You are in a good position ad-hoc connections and an NIAID-wide thing is the distance you have to travel to communicate with the community at principal investigators’ meeting every 18 to get to colleagues. But I don’t let it large about what science is good for. 'With months, RML scientists seem to be rea- stop me.” so much anti-intellectualism in the world sonably well plugged-in to NIAID. Chesebro says it would be nice to
. . . . we need to communicate about Broadcasts of the 'Wednesday Afternoon have the luxuriant selection of col- science. Here we have a better opportu- Lectures are available but poorly at- leagues from all scientific disciplines that nity to do that, compared with either a tended at the lab. More popular is RML’s are represented at a major medical cen- university or Bethesda.” Other scientists own lecture series and an open invita- ter—clinicians, chemists, neurobiolo- find Hamilton is much less stressful than tion to all RML staff to attend the an- gists, and mathematical modelers, for
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The N I H C a t a l 'i' ^ T
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example. Water-fountain meetings with Rocky Mountain Science a diverse range of people can lead to continuedfrom page 1 serendipitous discoveries of solutions. who have used careful cognitive test- But he notes that there’s only so much ing to differentiate HIV patients with Nestled 'neath the Bitterroots, the RML time; if he had a greater diversity of col- true AIDS dementia from those with parking lot is seretie ami spacious at 9 a.m. leagues with whom to chat, he’d prob- other neurological deficits caused by op- j it’s ably have less time for each. portunistic infections or other factors in lieve proven, but it might be the , A better setting for casual conversa- the disease. Through long-term studies, case,” he says. Priola, a virologist, ac- | tion is among the they have collected blood and knowledges that there is a lot of sup- improvements virus samples from living pa- porting evidence for the hypothesis, “But planned in the tients and brain samples from it is not entirely convincing. ... It is hard to find viruses in renovation that will deceased participants. These sometimes, but 1 include an interior materials have revealed that this case, no one is even looking.” courtyard connect- although almost 100 percent Chesebro comes down gently on the ing individual lab of patients die with active vi- side of the nonbelievers: “I’m not con- buildings. The ms present in their brains, just vinced that the transmissible agent is a protein only. In the case of the genetic original plan tar- 20 percent have AIDS demen- i geted only electri- tia. Cloning of the viais from TSE diseases, where people express mu-
cal and air-han- these patients has revealed tant PrP genes, these genes may be a i susceptibility factor, dling infrastmcture, that there are clear sequence but by no means ; Kindt says, but differences in do I believe we know the agent. I be- lieve when it was dis- the virus from the causative agent , covered that none demented and of TSE diseases is a vims; of the labs’ walls nondemented the fact that normal PrP in- |
' were up to modern patients. Be- teracts with PrP-res to i cause the indi- form amyloid is like pro- for earth- j code Celia Hooper quake-prone re- rect viral effects cesses that occur in many gions and that Willy Burgdorfer on neuronal cul- amyloid diseases, includ- "I would always come hack. there was lead tures correlate ing Alzheimer’s. But in ji^
paint and asbestos with effects in those diseases the protein i,;
to remove, the project grew into the living patients, Chesebro is alone won’t transmit the jJ disease,” as to present plan, which will replace or over- exploring, in vitro, what seems be ]; haul every lab by the year 2001. specific changes in HIV the case in TSE diseases But Burgdorfer says even the present envelope sequence—or at least under artificial conditions in which injec- facilities are hardly a drawback. “The the host's response to the Sue Priola renovation will add to our comfortable vims—result in damage to tion of the appropriate ' PrP-res into ani- quarters, though I am one of the few neurons. “It could be a combination of directly the brains of who appreciate the research facilities out cytokines, lipids, and envelope proteins mals will lead to disease. here’’ as they are. “I have set up labs produced by infected microglia that One of the most important break- under conditions you wouldn’t believe,” leads to damage to neurons,” Chesebro throughs in TSE research was made in he recalls. “I've dissected mosquitoes speculates. 1994 by Caughey, who first induced self- propagating conversion of with a toothpick in the tropics. . . . Here, Two other scientists in
' eveiything is furnished for you.” the LPVD interviewed by normally folded PrP to ab- normally folded PrP-res Ultimately, Burgdorfer says, it is not The Catalyst—Byron || fancy facilities or great hiking and wa- Caughey and tenure-track (so called because it is re- L sistant to proteases) in the terfalls that determine the fate of NIAID's investigator Sue Priola | Montana outpost. It’s “the intellectual fas- join Chesebro in his third test tube. This achieve- cination” and the lab’s ability to recruit interest in TSE diseases. ment was simultaneously and retain scientists who will sustain the 'While the three appear to an important proof-of- fascination and serve as magnets, attract- be very collegial, they principle for the prion hy- i pothesis and the basis for ing ideas and collaborators from all over. don’t even start out with j
" RML has been for Burgdorfer what the the same opinion of the fundamental techniques
unofficial slogan for the Bitterroot 'Val- prion hypothesis, namely for working with PrP. The ,
ley claims the area is: “The Last Best that abnormal prion pro- lab is now exploiting these s Place.” “I wouldn’t trade this for any tein, PrP-res, is sufficient techniques in basic and applied research. Caughey other area,” Burgdorfer says, referring as to transmit TSEs, which in- [ much to the lab’s research as the place clude bovine spongiform used this approach to , the in vitro reaction is ’ where it is conducted. “Lve gone abroad encephalopathy, scrapie in sheep and demonstrate that “incredibly specific.” In some instances a lot (with extended stays in Egypt, Lon- goats, and kuru and Creutzfeldt-Jakob \ in the test tube, PrP-res derived from don, and Czechoslovakia), “but I would disease in humans. Caughey comes ; always come back.” closest to being a believer: “I don’t be- one species of animal will convert PrP
September — October 1998
derived from a different species—but trations of gamma globulin Celia Hooper only in instances in which the same is and antibody to the virus. Vi- Bitterroot range serves as backdrop to RAIL animal true in vivo,, and cross-species trans- rus-antibody complexes de- facilities ( left foreground > mission of disease is possible. The lab posit in the kidneys, leading is finding that single- amino-acid differ- to kidney failure and death. blood test for Lyme disease and relaps- ences between different species’ strains Bloom expects various aspects of the ing fever and understanding the biol- of PrP are sufficient to block cross-spe- ADV system could shed light on chronic ogy of the spirochete inside the tick. Re- cies reactions. Now using infrared spec- infection states and autoimmune dis- lapsing fever, like Lyme, results when troscopy, Caughey has identified differ- eases—including human diseases such ticks transmit a spirochete, Borrelia ent P-sheet conformations in PrP-res that as lupus. In the mink system, the viral hermsii, to humans. Though uncom- might account for different strains of TSE capsid plays a key role in the disease. mon, relapsing fever is an insidious foe. agents. He is now trying to increase the In sharp contrast with other Ticks that transmit the bacteria are en- efficiency of the test-tube reaction so that parvovimses, “inoculating” mink with demic to the mountains in the West and a measurement can be made of whether empty capsid of ADV not only fails to are “fast feeders” that typically attach to new infectivity is generated by PrP-res protect the animals— it actually leads to a host at night and complete their feed- formation. The TSE research group is accelerated, hyperacute disease when ing in 10 to 90 minutes. Victims are un- also studying inhibitors of the reaction, the animals are challenged with live vi- likely to know they’ve been bitten or to including Congo red, sulfated glycans, ais. Bloom’s research group is now com- attribute their flu-like symptoms three peptide fragments of PrP, and phthalo- paring nonpathogenic and pathogenic to 10 days later to a tick bite; thus, their cyanines. These might yield clues to ADV isolates to understand precisely doctors are unlikely to take a blood therapeutic targets in TSE diseases and what structural features of the capsid sample, which would reveal the spiro- possibly other amyloidoses. convert the disease into such a bizarre chete in the blood. This first stage of Priola is using scrapie-infected cell cul- killer. As with Dengue fever, a key to the disease passes as antibodies clear tures and the in-vitro reac- the disease’s pathogenesis the infection. But that is not the last of tion to study the control of is ADV’s ability to infect Borrelia. Some days later the bacteria the passage of TSE from macrophages in the pres- turns to its genetic closet, stuffed with one animal to another and ence of antibody, and at least 40 different genes for outer sur- to look at the effects of hu- Bloom and his colleagues face proteins, switches to an antigeni- man familial TSE-associated are studying the mink’s cally fresh exterior, and again flourishes PrP mutations. Working cytokine responses—es- in the bloodstream, again making the with mouse and hamster pecially an IL-6 homo- victim sick. This process has been versions of TSE as models, logue—for clues to this known to repeat itself up to 12 times. Priola has pinpointed parts phenomenon. As much as Schwan believes the best hope for a vac- of the PrP amino-acid se- he still has to learn, cine lies in the surface of the spirochete quence that are critical in Bloom reckons ADV is as it is first transmitted from the tick. determining the compatibil- the best-studied of all Another research interest for Schwan ity of PrP isoforms from dif- parvovims diseases, and is how the bacteria that cause plague ferent species. In addition, he values the collegial re- sense and adapt to the molecular world Priola has described aber- lations of a small field. in their arthropod host—the flea. Key rations in the metabolism of mutant PrP “The advantage of working on Aleutian stimuli that turn off and on suites of molecules that may underlie pathogen- mink disease is that everyone working genes in Yersinia pestis are tempera- esis in familial TSE diseases. Currently on it in the world came out of or through ture, oxygen concentration, pH, and the one of Priola’s goals is to develop a di- my lab—all five of them!” arthropod’s ingestion of a blood meal. agnostic test based on Caughey’s test- The research of Tom Schwan, act- Work with RML postdoc Joe tube reaction that could be used to iden- ing lab chief for the Laboratory of Mi- Hinnebusch and Robert Perry of the tify animals that have BSE veiy early, crobial Structure and Eunction (LMSE), University of Kentucky in Lexington, before they show behavioral signs of carries on the historic focus of RML on published in Science, demonstrated that mad cow disease. blood-feeding arthropods and the the bacteria must possess and activate a Marshall Bloom, also of the LPVD, pathogenic bacteria they transmit to hu- certain set of genes to successfully in- has studied diverse aspects of the im- mans. But he gives the work a 21st-cen- fect the flea. Schwan points out that the munologically peculiar Aleutian mink tuiy twist by applying contemporary similar genes and processes—which disease parvovirus (ADV). ADV pro- techniques to understanding the may present attractive vaccine and di- duces different types of disease in new- bacteria’s molecular adaptations as they agnostic targets—are also likely to be born kits vs. adult mink. Infected kits move from the midgut, salivary glands, present other disease-causing agents typically succumb to fulminant respira- and other parts of cold-blooded ticks transmitted by arthropods. tory infection, similar to hyaline mem- and fleas into a dramatically different LMSE tenure-track investigator Patti brane disease of premature human in- environment: the warm bloodstream of Rosa says that to begin to understand fants. Adults develop a persistent infec- mammals. gene regulation and adaptation in Bor- tion, forming massive numbers of lym- A primary interest for Schwan is in relia burgdorferi, the agent that causes phocytes and extremely high concen- spirochetes: developing an improved Lyme disease, will first require devel-
9 The NIH Catalyst
Oping molecular for exploring how host and spirochete coupled with mo- tools for manipulat- respond to one another. Porcella, a life- lecular immunol- ing the spirochete’s long rock-climbing and mountaineering ogy, could provide genome similar to enthusiast, says, “I like big challenges. a uniquely com- tools that have made Working with syphilis is a lot like climb- plete profile of the Escherichia coli. and ing a big granite wall—it seems impos- infectious process }'. pest is tractable. sible at first, yet if you chip away at it, for the spirochetes An important step is you eventually reach your goal.” Another Porcella studies. finding a plasmid big challenge is a project perfecting what Porcella adds that that replicates reli- Porcella calls “bionic mice.” These ani- for a postdoc at ably in the spiro- mals are implanted interperitoneally with RML, “the senior chete and can serve an FM transmitter that provides an in- staff, the support as a ferry for genes. stantaneous and continuous record of staff, and the facili- With a small set of genetic tools in hand, the animals’ activity and body tempera- ties—everything is
Rosa has begun to knock out genes to ture. The system produces an intimate the best. . . . The opportunities to try an.swer biological questions: What genes record sensitive enough to demonstrate new, innovative science, or even risky play a critical role in the ability of the physiological effects of simply chang- approaches to age-old questions make
Lyme disease spirochete to adapt to vari- ing the animal’s bedding material. If it a real joy to work here. To me, this ous environments? How does its gene some technical bugs can be ironed out, place really is Shangri-La.” expression change between tick and long-term data from the bionic mice. —CH mammalian hosts? Postdoc Steve Porcella works on bac- RML Scientists Develop Anti-Rabies DNA Vaccine terial expression and host response in ML sdenti.sts have developed a DNA vaccine against rabies that protected all of vivo to spirochetes that cause Lyme dis- Reight vaccinated monkeys against the disease. This is the first DNA vaccine to show ease, fever, syphilis ( Tre- relapsing and complete protection in nonhuman primates against a virus that attacks the central ner- ponema pallidum). The latter work is vous system. daunting because the spirochete can “The vaccine worked beyond our wildest dreams,” commented lead author Donald only be grown in the rabbit testis and Lodmell, of the NIAID Laboratory of Persistent "Viral Diseases, following publication of development of a molecular genetic sys- a report in the August issue of Nature Alediciiie. tem for manipulating the bacteria has Postdoc Nancy Ray made the vaccine from DNA encoding the surface glycoprotein of the rabies virus. Not only did the vaccine afford perfect protection against lethal proven intractable. The labile bacteria doses of the virus, it elicited anti-rabies antibodies that neutralized a global range of deteriorate rapidly outside of the rabbit rabies viruses, a result that suggests the vaccine will be effective worldwide testis, which Porcella uses as his model —from a press release by Laurie Doepel, NIAID
10
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Septemiser — October 1998 Hot Methods
Making the Short List: by Doug Loftus. NCI How TO Succeed in Getting a Job Interview by Really Trying
f you’ve submitted teaching experience, nary speaker at symposia. For an industiy papers for critical any administrative ex- position, this type of narrative can be help- I peer review, you perience, awards, pro- ful to the employer and should be in- know that it can be fessional society mem- cluded. However, especially for academic humbling and not a berships, and grants (if positions, Landis advocated a more eco- little anxiety provoking. any; postdocs early in nomical approach: Give them precisely What could be expo- their careers might con- what they ask for—no more, no less. nentially worse, how- sider applying for a K22 Research statement. ( for academic ever, is submitting not award; see
11 The NIH Catalyst
People Recently Tenured
ing, we have also demonstrated that ROS membrane material and are compatible Toren Finkel received his M.D. and serve as mediators of apoptosis. Using with investigation of complex biologi- Pb.D. from Harvard Medical School in an adenovims to deliver wild-type p53, cal membranes containing mixtures of in Boston in 1986. He completed a resi- we have demonstrated that p53 expres- lipids and proteins at physiological con- dency i)i internal medicine at the Mas- sion results in an increase in ROS, which ditions. With atomic resolution, we are sachusetts General Hospital in Boston is needed to initiate apoptosis. More re- able in many instances to pinpoint the and a cardiology fellowship at Johns cently, we have shown that ROS also location of membrane molecules in the
Hopkins University i}i Baltimore before mediate certain aspects of senescence. lipid matrix. joining the NHLBI Cardiology Branch in Taken together, these results suggest For example, we determined that cell is 1992. He is currently a senior investiga- that the redox state of the actively short-chain alcohols such as ethanol tor and chiefofthe Cellular and Molecu- regulated and plays an important role in locate preferentially near the membrane- lar Biology Section in that hra)ich. a variety of pathways as diverse as water interface and lower interfacial en- Atherosclerotic heart dis- growth, death, and senes- ergy of lipids and proteins. These tech- ease remains the leading cence. The mechanism by niques enable a more detailed descrip- cause of morbidity and mor- which small diffusible mol- tion of membrane biophysical proper- tality in the Western world. ecules like H 2 O, can regulate ties, including parameters that describe Over the past 20 years, many targeted pathways is not yet the energy of elastic membrane defor- studies have demonstrated fully understood. We are cur- mation, that can be linked to the mem- the role of blood pressure, rently seeking to identify spe- brane receptors’ stmctural transitions smoking, cholesterol, and cific intracellular protein tar- during excitation. other factors in disease pro- gets of ROS. Furthermore, we The alteration of membrane mechani- gression, but relatively little hope to relate these findings cal properties is one possible role of is known about how these back to the vessel wall to un- lipicl polyunsaturation. There has been Toren Finkel systemic factors result in lo- derstand how continuously controversy concerning the nature of the calized plaque formation. elevated concentrations of ROS contrib- perturbation of membrane elasticity in- Before the development of atheroscle- ute to atherosclerotic disease progres- duced by DHA chains. The six methyl- rotic plaque in both animal models and sion. ene-interaipted cis double bonds within human subjects, however, there appears DHA’s 22-carbon unit reduce the num- to be an increase in the production of Klaus Gawrisch received his Ph.D. in ber of degrees of freedom for structural transitions, a finding that has led reactive oxygen species (ROS) from the physicsfrom Leipzig ( Germany) Univer- some vessel wall. My lab has focused on how sity in 1979. He received further train- investigators to suggest that these chains these ROS are generated and regulated ing in membrane biophysics and nuclear have a specific, rigid conformation. in nonphagocytic cells and what intrac- magnetic resonance (NMR) at Leipzig However, this hypothesis is at variance ellular signaling pathways they seem to University and at NLH—at DCRT and as with experimental results. We deter- regulate. a visiting scientist at NHLBL. Ln 1993, he mined, for the first time, a large num- that describe orien- Early in our studies, we observed that moved to the NLAAA Laboratory ofMem- ber of parameters vascular smooth muscle cells stimulated brane Biochemistry and Biophysics, tation and motion of individual DHA by platelet-derived growth factor (PDGF) wber-e he now heads the NMR section. chain segments in biomembranes, and produce a large and rapid but transient My team investigates the in- we measured by X-ray diffrac- tion average chain . DHA increase in intracellular H 2 O 2 We were fluence of the lipid matrix on able to demonstrate that this increase in the function of neural recep- length and the molecular ROS was essential for PDGF signal trans- tor proteins, in particular, the cross-sectional area. The duction and, in particular, for growth influence of high concentra- data indicated an unex- factor-stimulated tyrosine phosphoryla- tions of polyunsaturated fatty pected high deformability of tion. Results from our lab and others acids, such as the unsaturated DHA chains. This informa- have since suggested that the burst of docosa-hexaenoic acid ( DHA, tion provided constraints by ROS is not confined to smooth muscle 22:6n3) with six double which to examine DHA cells or PDGF, but occurs with a variety bonds. The phospholipids of conformations proposed by of ligands in a multitude of cells. brain synaptosomes and the molecular modeling studies Klaus Gawrisch We next were able to demonstrate the retina contain 30 to 50 mol% to determine their correla- role of the small GTPases ras and rad DHA as fatty acids. Several tion with experimental data. in the regulation of ligand-stimulated lines of evidence suggest that high DHA Our results suggest that DHA chains ROS. This was particularly interesting concentrations are necessaiy to achieve in membranes prefer looped conforma- because rac proteins were already full activity of certain neural membrane tions and undergo rapid structural tran- known to regulate ROS production in receptors. sitions, providing increased flexibility to nonphagocytic cells. Nonetheless, these I have applied recent developments receptor-rich neural membranes. More- results suggested that the ras superfam- in NMR spectroscopy to the study of over, our research is beginning to un- ily of proteins might function to regu- membrane structure and dynamics to cover a framework within which the late the balance of oxidation and reduc- obtain a better description of membrane biophysical properties and functions of tion, that is, the redox state, of the cell. properties that modulate membrane re- membrane lipids can be understood in Not only does our work suggest that ceptor function. Modern NMR techniques terms of their degree of unsaturation, a ROS play a role in growth-factor signal- require only milligram-size samples of discrimination that nature clearly makes.
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S E I' r E M b E R — O C T O B E R 19 9 8
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get homeotic genes and have used ge- (sn ) RNA, but their promoter genes are James Kennison received bis Ph.D. netic screens to identify other proteins organized differently from those of tRNA from the University of Califoniia, San that interact with BRM in regulating these and Alu and engage different arrays of Diego, in 1979 and did postdoctoral target genes. BRM appears to interact pol III transcription factors. Several vi- work at the Universidad Aiitonoma de with different sets of proteins at these ruses rely on pol III for the expression Madrid, the University of Alberta in two cis-regulatory elements. of their small RNA genes, most notably Edmo)iton. and the University of Colo- Complementing our work on the pro- adenovinis, whose virus-associated [VA] rado in Boulder beforejoi)ii}ig tbe Labo- teins that maintain transcriptional acti- RNA products modulate the host-cell ratoiy of Molecular Goietics of NICHD vation of the homeotic genes, we are translational machinery. A growing num- in 1987. He is now a senior investiga- now also identifying and characterizing ber of pathogenic vimses not only use tor in the Sectio)i on Developmental Bi- proteins required to maintain repression pol III for expression of their genes, but ology. of these genes. One of these also encode proteins that modulate cer- I have a long-standing in- new repressors appears to be tain host-cell pol Ill-associated factors. terest in how cellular diver- part of a histone deacetylase Nearly one million Alu sequences sity is established and main- complex, which suggests a constitute a complex family of mobile tained. As a confirmed role for histone deacetylation elements that “retro”-transpose through Drosophila geneticist, I in maintaining repression of their small RNA transcripts, sometimes have used the sophisticated the homeotic genes. causing recognizable genetic disorders genetics of the fruit fly We began exploring faiit fly in humans. These sequences, like the Drosophila melanogaster to development in the hope that family of tRNA genes, contain pol III identify and characterize the our observations would elu- promoters within their transcribed re- Fran Pollner genes involved in one par- cidate how genes control hu- gion, a feature that endows newly in- ticular developmental step, James Kennison man development. Because serted copies with the potential for tran- the specification of segmen- not only the homeotic genes scriptional competence. However, un- tal identity in the fly. Segmental identity but also the proteins that regulate their like other pol Ill-transcribed sequences, is specified by the homeotic genes, the function appear to be conserved be- Alu elements are maintained in a tran- Drosophila homologues of the HOX tween flies and humans, we are finding scriptionally inactive state, becoming genes of vertebrates. Because the that our hopes have not been misplaced. activated by viral infection, heat shock, homeotic genes have 100-kb cis-regu- Moreover, the emergence of increasingly and translational stress. The mechanisms latory regions that control their devel- sophisticated molecular genetic ap- that regulate Alu transcription and the opmental expression patterns, a large proaches in Drosophila bolsters our con- consequences of their expression are number of proteins are required to fidence that this research will continue largely undefined. specify and maintain expression. I have to expand our understanding of human Assembly of a transcription complex concentrated on identifying and char- developmental processes, both normal on the promoter of a target gene is a acterizing two groups of genes that func- and defective. key determinant of eukaiyotic gene tran- tion to maintain patterns of gene activ- scription—but it is not the only one. My ity, either repression or activation. These Richard Maraia received bis M.D. from laboratory has shown that control can two groups of genes, the Polycomb and Cor)iell University Medical College, New also occur at the levels of transcription trithorax, are consei-ved between Droso- York, in 1985. He completed a pediatric termination and reinitiation. Efficient phila and humans. residency at New York. Hos- reinitiation is especially im- My colleagues and I have identified pital before coming to NIH i)i portant for tRNA and 5S more than a dozen new Polycomb and 1987, when he was jointly rRNA genes that must be trithorax group genes using genetic appoiiited by the Hitma)! Ge- transcribed at high levels. We screens. We have cloned and character- netics Branch, NICHD, a):d have focused on the human ized several of these new genes, includ- the Interinstitiite Medical Ge- La protein, an abundant ing the brahma (brni) gene. We showed netics Program as a medical nuclear phosphoprotein that
that the BRM protein functions as the staff fellow. In 1990, he be- is recognized as a self-anti- ATPase subunit of a 2-megadalton pro- came afounding member of gen in patients suffering from tein complex. This complex is conserved the Laboratory of Molecular autoimmune disorders such from yeast to humans and appears to Growth Regulation, NICHD, as systemic lupus eiythema- be a chromatin remodeling machine. We where he is now a senior in- tosus and Sjogren’s syn- have shown that BRM is required to vestigator. drome. We have shown that maintain expression not only of the My current research uses RNA poly- La facilitates transcriptional termination
homeotic genes but of several other im- merase (pol) III and its associated fac- and reinitiation by pol III. Moreover, as portant developmental genes as well. It tors as a model to explore the mecha- an RNA-binding protein that remains as- is not required for expression of all nisms that control transcription in eu- sociated with nascent pol III transcripts Drosophila genes, however. karyotes and to elucidate how the ex- after their synthesis. La also controls the We are currently trying to understand pression of certain small RNA genes post-transcriptional processing of these what recmits this large protein complex namely tRNA and Alu family RNAs. We have shown that human La is to its target genes. We have identified retroposons—are regulated. Pol III also phosphorylated on serine 366, an evo- putative &/7»-response elements in the synthesizes a variety of other transcripts, lutionarily conserved casein kinase II cis-regulatoiy regions of two of the tar- including 5S rRNA and U6 small nuclear phosphorylation site, and that this pro-
13 1 s T ill- N H C \ T A I V r
E 0 P L E Recently Tenured
cess can regulate La’s ability to modu- entiate it from other objects within the premise that the distinction between late transcription as well as RNA pro- same semantic category (for example, members of different categories of ob- cessing. Thus, the human La phospho- information about the features that dis- jects depends on access to information protein can coordinate and regulate tran- tinguish a tiger from a leopard or a pair about different types of features. More scriptional and post-transcriptional steps of pliers from a wrench). generally, these studies have provided in RNA biogenesis. LJsing functional brain imaging with us with a means for asking questions Our team has developed a pol III tran- normal subjects, we have been able to about the broader issue of how infor- scription-termination reporter gene in demonstrate that information about dif- mation is stored and organized in the the fission yeast Schizosaccharomyces ferent types of features, such as an human brain. pombe for use in our continuing stud- object’s typical shape and color, is not ies. We use a tRNA opal suppressor ca- stored as a whole unit in a specific place Stanko Stojilkovic received his Ph.D. pable of suppressing a nonsense codon in the brain. Rather, this information is in 1982 from the University ofNovi Sad, so that the mRNA can encode a colori- distributed in the brain and organized Yugoslavia, where he was an assistant metric metabolic marker (Ade6-704). We into a network of discrete cortical re- professor ofa}iimalphysiology untiljoin- plan to examine intracellular signals that gions: Different features and attributes ing the NICHD 's Endocrinology and Re- can integrate the phosphorylation sta- are stored near the regions of the brain production Research Branch i)i 1985. tus of La with pathways relating to other that mediate perception of those at- In 1993, he became an investigator and aspects of cell biology and proliferation. tributes. Thus, for example, knowledge head of the Unit on Cellular Signalijig
Our goal is to use information gained of object color is stored in a i}j that branch. from this system to advance our under- region of the brain adjacent The research in my labo- standing of gene regulation and cell to the areas that mediate per- ratory has focused on under- growth in humans. ception of color, whereas standing the mechanisms knowledge about object mo- and functions of calcium sig- Alex Martin receireci his Ph.D. from tion is stored adjacent to ar- naling in hypothalamic and City University ofNew York in 1978. He eas that mediate motion per- pituitary cells. did his postdoctoral work at NINCDS ception. These findings dem- Earlier investigations re- (now NINDS) on cognitive dysfunction onstrate a close link between vealed that two calcium-sig- in patients with Alzheimer's disease be- brain that medi- in areas of the Fran Pollner naling pathways operate fore joining the faculty of )wnrology at ate perception of different vi- tcmko Stojilkovic hypothalamic and pituitary DoD's [Jniformed Services University of sual features (form, color, cells: plasma membrane the Health Sciences, where he concen- and motion) and the regions of the brain (PM)- and endoplasmic reticulum (ER)- trated on cognitive and motor dysfunc- where we store these types of informa- derived. I have shown that these cells tion associated with different stages of tion. Additional studies have shown that express a set of voltage-gated channels HIV ijfection. In 1990, hejoined NIMH a similar link exists between brain re- that drive spontaneous action potentials, and is currently a se)dor investigator in gions that subserve motor performance leading to cytosolic calcium fluctuations the Laboratory (fBrain and Cogidtion. and stored knowledge about how ob- (the PM oscillator). The major thrust of My interests lie in the area jects are used. Thus, the or- these investigations was on the role of of cognitive neuroscience, ganization of semantic infor- dihydropyridine-sensitive channels in specifically as it relates to mation parallels the organi- calcium signaling and the mechanism understanding perceptual zation of the sensory and of their activation and inactivation. and memoiy systems. My motor systems in the primate ER-derived calcium signaling in hy- recent research at NIMH brain. pothalamic and pituitaiy cells is activated uses functional brain imag- These studies have pro- by several hypothalamic calcium-mobi- ing technologies, positron vided us with a deeper un- lizing agonists. Agonist-induced calcium emission tomography, and derstanding of object-recog- release from the ER is mediated by inosi- function magnetic reso- nition, object-naming, and tol 1,4,5-trisphosphate and leads to fre- nance imaging to evaluate language-comprehension quency-modulated oscillatory calcium the functional neu- problems in a variety of brain signaling in gonadotrophs (the ER os- roanatomy of semantic disorders, including Alz- cillator) and to nonoscillatory amplitude- memoiy—a specific type of memoiy heimer’s disease and related dementias. modulated calcium signaling in lacto- system that includes the information They have also provided us with a trophs (lactotrophs and gonadotrophs stored in our brain about the meaning framework for understanding the etiol- are pituitaiy cells that produce hormones of words and objects. ogy of category-specific knowledge dis- that control lactation and ovulation and Our earlier studies sought to clarify orders that result from focal brain le- spermatogenesis, respectively).
word comprehension and word-finding sions (for example, how one patient can I have characterized the role of sev- problems—such as an inability to re- have problems naming and retrieving eral intracellular elements involved in trieve object names—in patients with information about a single category of the regulation of the oscillatory vs. Alzheimer’s disease. We learned that objects, such as four-legged animals, and nonoscillatoiy calcium response, such such difficulties are related to a loss of another patient can have a deficit lim- as inositol 1,4,5-trisphosphate receptor information about the features and at- ited to naming and knowing about channels and the ER calcium pump. I tributes that define an object and differ- tools). This framework is based on the have also studied the coupling of PM
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and ER oscillators during agonist stimu- ternative splicing, generating several calcium release from intracellular stores lation. These experimental studies led isoforms. We have identified the amino- and action-potential-driven calcium influx. to the development of quantitative math- acid residues contributing to the desen- Our recent finding that endothelin, ematical models—one for the PM oscil- sitization of the P2X2 subtype of these unlike other calcium-mobilizing ago- lator and one for the ER oscillator—as channels, or the protective attenuation nists, induces a prolonged inhibition of well as a coupled model that describes of response during prolonged ATP electrical activity—with associated de- the effect of the PM oscillator on deple- stimulation. The finding that these resi- creases in calcium influx and cytosolic tion and repletion of the ER calcium dues are also expressed in all slowly calcium, depletion of the ER calcium pool. Eunctional studies have shown that (but not rapidly) desensitizing P2X chan- pool, and inhibition of prolactin re- both hormone release and gene tran- nels suggests that a common mechanism lease—piqued our interest. Preliminary scription can be activated by calcium- controls the rate of cationic influx pharmacological investigations suggest mobilizing agonists when the PM oscil- through these channels, a hypothesis that a novel endothelin receptor is ex- lator is rendered inoperative by the that will be tested in the near future. pressed in lactotrophs. We are now at- depletion of extracellular calcium. In the We recently identified a novel calcium- tempting to clone this receptor. Eunc- absence of an agonist, spontaneous ac- influx pathway in several excitable cells tional characterization and coupling of tivity of the PM oscillator is sufficient to that is activated by depletion of the ER this novel receptor to intracellular mes- trigger hormone release and early-re- calcium pool in a manner comparable sengers will follow. sponse gene expression in lactotrophs to that observed in nonexcitable cells. Another of our objectives is to under- but not in gonadotrophs. In neuroendocrine cells, these calcium- stand the link between the cellular func- Current investigations focus on two influx channels also depolarize the tions and dynamics of calcium signal- families of plasma-membrane calcium plasma membrane to generate action po- ing in isolated and interconnected cells. channels. We recently found that ATP- tentials or to increase the frequency of The studies will focus on physiological gated purinergic-receptor (P2X) chan- spiking in spontaneously active cells. requirements for the specific pattern of nels are expressed in pituitary cells and C3ur current investigations are directed calcium signaling (oscillatory vs. have the capacity to modulate PM- and toward characterizing the electrophysi- nonoscillatoiy), the source of calcium ER-derived calcium signals and secre- ological properties of these channels in (PM- and ER-derived), the threshold tion. The primary P2X gene transcripts hypothalamic and pituitary cells, as well calcium concentration needed to acti- in pituitary cells undergo extensive al- as the mechanism of synchronization of vate a specific cellular process, and the role of calcium signals in synchroniza- Interest Group Gazette tion of cellular activity among neural and nonneural networks. A Cold Day with the Mitochondria “Mitochondria: Genetics, Elealth, and Disease,” an all-day minisymposium December 2, 1998, is being held in conjunction with a Wednesday Afternoon Right Interest Group Lecture and is sponsored by the NIH Interinstitute Mitochondria Interest Wrong Contact Name Group (MIG). Lectures will be held at Masur Auditorium in the Clinical Center Please correct the spelling of my (CC); posters and exhibits will be displayed at the Visitor Information CC name as a contact for the Image Center, CME credit is available. Processing Interest Group. Meals, breaks, and reception are sponsored by the Technical Sales Associa- —Beiws Triis, CIT tion. A block of rooms at a special meeting rate has been reserved at the Phone: 496-2250 Bethesda Ramada. Call 800-272-6232, or 301-654-2703, before November 9, E-mail:
An Organismfor All Seasons “Choosing an Organism: The Ins and Outs of Developmental Genetics in the Eukaryotic Hierarchy” is the theme of the fall-winter meetings of the Genetic s Interest Group. The series is designed to help researchers select their model organism and includes speakers from NIDDK, NICHD, NINDS, NIDCD, and NHGRI. Meetings are held Tuesdays at 4:00 (except December 15, which starts at 4:30) in Building 49, Conference Rooms A & B. September 15: Nematode October 13: Zebrafish November 10: Drosophila December 15: Xenopus January 12: Avian Eebruary 9: Mouse March 9: Human Eor additional info, contact Beverly Mock at e\ @helix.nili.goA> or Lynn Hudson at
Benoit Leblanc, NIDDK
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Call for Catalytic Reactions
n this issue, we are I asking for your reactions 1 ) The Catalyst's Editorial Advisory Board has urged us to present more science tidbits in four areas: “Catalytic along the lines of the Rocky Mountain Lab Science Sampler (this issue) or the pieces in the Cauldron,” Research "Recently Tenured” section. What research subjects would you most like to read about in Festival ideas, achieving our upcoming “Catalytic Cauldron” section? CV perfection, and “hot methods.”
Send your responses on 2) What innovations would you like to see in the 1999 Research Festival? What worked well these topics or your (and not so well) in 1997 and 1998? comments on other intramural research concerns to us via e- maU:
In Future Issues...
_ Al Graeff Helps CIT Find ITself 4) What would you like to see elucidated in a future “hot methods” article? What were the "hottest methods,” ideas, or research you happened upon at the Research Festival, October Fogarty Scholars _ 6-9? Link NIH Labs
Y2K + U = X
The NIH Catalyst is pub- PUBUSHER SciENTinc Editor Editorial Advisory Board lished bimonthly for and by Michael Gottesman Celia Hooper Jorge Carrasquillo, CC the intramural scientists at Deputy Director David Davies, NIDDK NIH. Address correspon- for Intramural Research, OD Managing Editor Dale Graham, DCRT dence to Building 1, Room Fran Pollner Hynda Kleinman, NIDR 209, NIH, Bethesda, MD Editor Elise Kohn, NCI 20892. Ph: (301) 402-1449; Lance Liotta Copy Editor Susan Leitman, CC fax: (301) 402-4303; Chief, Laboratoiy of Pathology, Shauna Roberts Bernard Moss, NIAID e-mail:
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